1. Field of the Invention
This invention relates to a pharmaceutical tablet containing polyvinyl pyrrolidone (PVP) as a binder for a pharmaceutically-active ingredient therein, and more particularly, to such tablets which dissolve readily in water to release their active material even after the product has experienced a considerable period of shelf-time.
2. Description of the Prior Art
Polyvinylpyrrolidone (PVP) also is used widely as a binding agent for pharmaceutical tablets. However, it is essential that the PVP binder itself not interfere with the normal dissolution rate of the tablet in water. Suitable PVP polymers presently used as a binder agent in pharmaceutical tablets are prepared by free radical polymerization in the presence of a free radical initiator, as described in Polymer Journal 17, No. 1, p 143-152 (1985). These free radical polymerization initiators are used in amounts of about 0.05 to 10% by weight of the monomer, and, preferably about 0.1 to 5% by weight of an initiator is required. Hydrogen peroxide, di-t-butyl peroxide, dicumyl peroxide, t-butylperoxy pivalate (TBPP) and t-butylperoxy benzoate (TBPB) are widely used free radical polymerization initiators for the preparation of PVP polymers. TBPP, for example, undergoes thermal homolysis to produce t-butoxy and t-butyl free radicals by the following mechanism shown below. ##STR1## whereupon .beta.-scission of the t-butoxy radical produces the methyl free radical: ##STR2##
Thus, the active free radical species for initiation of free radical polymerization are: ##STR3##
The methyl and t-butoxy free radicals, respectively, have high bond dissociation energies (BDE) of 104 and 105 kcal/mole, respectively. Therefore, these radicals can readily abstract a labile hydrogen atom from the PVP polymer to transfer the site of initiation and hence convert an otherwise linear polymer into a branched polymer. If this process is carried too far, the PVP polymer produced will have poor water solubility and/or become gels. In addition, the half-life of such TBPP initiator, i.e. the time at a given temperature to effect a loss of one-half of the perester's active oxygen content, is a lengthy 24.6 hours at 50.degree. C. Accordingly, TBPP requires a high reaction temperature, e.g. 60.degree.-80.degree. C., to carry out the polymerization within a reasonable period of time. Accordingly, the choice of initiator is critical to preclude the formation of branched rather than linear PVP polymers both during polymerization and afterwards during ageing of pharmaceutical tablets containing PVP as a binding agent.
Straub, in U.S. Pat. No. 4,433,112, shows that residual initiators, especially of higher energy, can cause crosslinking of PVP even after VP is used up; therefore, there is no reason not to believe that the same thing can readily happen during polymerization. In free radical polymerization, at any instant, there is only completely formed polymer and unreacted monomer. The molecular weight of the polymer does not build with time as in polyesters. Therefore polymer is available from the onset of polymerization to be attached by initiator to cause branching and crosslinking.
Accordingly, it is an object of this invention to provide a pharmaceutical tablet containing a suitable PVP polymer as a binding agent which PVP can dissolve readily in water even after a prolonged shelf-life of the tablet.
It is another object of this invention to provide a pharmaceutical tablet using PVP as a binding agent which PVP is made by a polymerization process using a free radical initiator whose thermal homolysis reaction or redox reaction provides free radicals which because of temperature or structure are weak hydrogen abstractors, and which exhibit relatively poor electron transfer to the PVP polymer, whereby a substantially linear, non-crosslinked PVP polymer can be obtained having a high degree of water solubility even under extreme storage conditions.